The use of genotyping to identify human papillomavirus (HPV) infections has linked specific HPV types to benign, premalignant and malignant lesions of the oral cavity. Although HPV infections are necessary for development of up to 50% of oral squamous carcinomas, co-factors such as tobacco, alcohol and depressed immunity are also required for conversion of premalignant to malignant lesions. Prevention of HPV infections by vaccination would eliminate these lesions and their malignant sequelae, regardless of the presence of co-factors. Mucosotropic HPV that infect the oral cavity are not produced in large quantities in vivo and are nonpropagable in tissue culture, precluding the use of authentic virions as the source of a vaccine. However, a highly reproducible animal model exists for prevention of oral cavity papillomas by vaccination. The canine oral papillomavirus (COPV) vaccine, consisting of either live or formalin-fixed homogenates of COPV-induced papillomas inoculated intradermally, has effectively vaccinated over 150,000 beagles, 25% of which would otherwise develop papillomas as weanlings. We are currently producing recombinant COPV major capsid protein (MCP or L1) and L1 and minor capsid (L2) protein viral-like particles (VLPs) to use as a preventive vaccine in beagles. Recombinant BPV L1 VLPs produce high titered neutralizing antibodies against BPV virions, whereas BPV L2 proteins are reported to be effective in enhancing cell-mediated immunity (CMI) responsible for regression of BPV (the prototype PV) induced fibropapillomas in cattle. Our goals are to use the canine animal model system to evaluate T cell proliferative responses to recombinant L1 and L1 and L2 VLPs. The CD4 + T cell responses will be compared with the clinical effectiveness of and serologic positivity to: 1) The current, effective, homogenate vaccine, 2) recombinant subviral vaccines (VLPs composed of L1 and L1 and L2 proteins), and 3) vaccination with authentic, empty (no viral genome) COPV capsids. We will also evaluate the T helper response associated with spontaneous regression of papillomas in naive dogs inoculated with infectious COPV. It is anticipated that evaluating T helper activity in conjunction with our current studies of antibody responses to COPV L1 and L2 proteins in vaccinated or infected Beagles will provide insight into an appropriate approach for prophylactic and therapeutic HPV VLP vaccines to prevent development of up to 50% of oral cancers in humans, thus negating the effect of putative co-factors.